Investigation of the binding and dynamic features of A.30 variant revealed higher binding of RBD for hACE2 and escapes the neutralizing antibody: A molecular simulation approach

Shafiq, Athar; Zubair, Farrukh; Ambreen, Amna; Suleman, Muhammad; Yousafi, Qudsia; Niazi, Zahid Rasul; Anwar, Zeeshan; Khan, Abbas; Mohammad, Anwar; Wei, Dong‐Qing

doi:10.1016/j.compbiomed.2022.105574

Cited by 4 publications

(3 citation statements)

References 57 publications

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“…This suggests a notable variation in the NSP6 variants compared to the wild type, aligning with previous studies on different SARS-CoV-2 variants that also pointed to increased vdW energy. Another crucial factor, the electrostatic energy, was reported to be responsible for the enhanced binding of various variants in prior research ( Suleman et al, 2021b ; Shafiq et al, 2022 ; Suleman et al, 2023b ). In the current study, similar observations were made as the wild type exhibited an electrostatic energy of −1059.82 kcal/mol.…”

Section: Resultsmentioning

confidence: 97%

Elucidating the binding mechanism of SARS-CoV-2 NSP6-TBK1 and structure-based designing of phytocompounds inhibitors for instigating the host immune response

Suleman,

Ishaq,

Khan

et al. 2024

Front. Chem.

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SARS-CoV-2, also referred to as severe acute respiratory syndrome coronavirus 2, is the virus responsible for causing COVID-19, an infectious disease that emerged in Wuhan, China, in December 2019. Among its crucial functions, NSP6 plays a vital role in evading the human immune system by directly interacting with a receptor called TANK-binding kinase (TBK1), leading to the suppression of IFNβ production. Consequently, in the present study we used the structural and biophysical approaches to analyze the effect of newly emerged mutations on the binding of NSP6 and TBK1. Among the identified mutations, four (F35G, L37F, L125F, and I162T) were found to significantly destabilize the structure of NSP6. Furthermore, the molecular docking analysis highlighted that the mutant NSP6 displayed its highest binding affinity with TBK1, exhibiting docking scores of −1436.2 for the wildtype and −1723.2, −1788.6, −1510.2, and −1551.7 for the F35G, L37F, L125F, and I162T mutants, respectively. This suggests the potential for an enhanced immune system evasion capability of NSP6. Particularly, the F35G mutation exhibited the strongest binding affinity, supported by a calculated binding free energy of −172.19 kcal/mol. To disrupt the binding between NSP6 and TBK1, we conducted virtual drug screening to develop a novel inhibitor derived from natural products. From this screening, we identified the top 5 hit compounds as the most promising candidates with a docking score of −6.59 kcal/mol, −6.52 kcal/mol, −6.32 kcal/mol, −6.22 kcal/mol, and −6.21 kcal/mol. The molecular dynamic simulation of top 3 hits further verified the dynamic stability of drugs-NSP6 complexes. In conclusion, this study provides valuable insight into the higher infectivity of the SARS-CoV-2 new variants and a strong rationale for the development of novel drugs against NSP6.

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Section: Resultsmentioning

confidence: 97%

Elucidating the binding mechanism of SARS-CoV-2 NSP6-TBK1 and structure-based designing of phytocompounds inhibitors for instigating the host immune response

Suleman,

Ishaq,

Khan

et al. 2024

Front. Chem.

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“…Celik et al evaluated SARS-CoV-2 variants, including Iota, Mu, Delta plus, Kappa, Lambda, and C.1.2 for their changes in the interacting residues between spike-RBD region and hACE2 receptor, and highlighted the increase in the stability of the interacting complex as compared to the wild-type, leading to enhanced virulence [ 9 ]. Furthermore, Shafiq et al demonstrated that one of the SARS-CoV-2 variants in Tanzania, the A.30 strain, manifesting the mutations R346K, T478K, and E484K in the Spike-RBD region, aids the virus with immune escape properties [ 51 ]. The Omicron variant, harbours a large number of mutations in the RBD region of the spike protein, including K417N, G446S, Q493R, and Q498R, leading to more stable interactions with the hACE2 protein [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 VOCs, Mutational diversity and clinical outcome: Are they modulating drug efficacy by altered binding strength?

et al. 2022

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“…The newly emerged A.30 variant contains the T478R and E484K mutations. Among them, E484K is found to be responsible for developing resistance against antibody‐mediated neutralization [38]. Recently circulating VOCs are Omicron variants and their different lineages.…”

Section: Introductionmentioning

confidence: 99%

A multi‐tier computational screening framework to effectively search the mutational space of SARS‐CoV‐2 receptor binding motif to identify mutants with enhanced ACE2 binding abilities

Chakraborty,

Saha

2023

Molecular Informatics

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SARS‐CoV‐2 gained crucial mutations at the receptor binding domain (RBD) that often changed the course of the pandemic leading to new waves with increased case fatality. Variants are observed with enhanced transmission and immune invasion abilities. Thus, predicting future variants with enhanced transmission ability is a problem of utmost research interest. Here, we have developed a multi‐tier exhaustive SARS‐CoV‐2 mutation screening platform combining MM/GBSA, extensive molecular dynamics simulations, and steered molecular dynamics to identify RBD mutants with enhanced ACE2 binding capability. We have identified four RBM mutations (F490K, S494K, G504F, and the P499L) with significantly higher ACE2 binding abilities than wild‐type RBD. Compared to wild‐type RBD, they all form stable complexes with more hydrogen bonds and salt‐bridge interactions with ACE2. Our simulation data suggest that these mutations allosterically alter the packing of the RBM interface of the RBD‐ACE2 complex. As a result, the rupture force required to break the RBD‐ACE2 contacts is significantly higher for these mutants.

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Investigation of the binding and dynamic features of A.30 variant revealed higher binding of RBD for hACE2 and escapes the neutralizing antibody: A molecular simulation approach

Cited by 4 publications

References 57 publications

Elucidating the binding mechanism of SARS-CoV-2 NSP6-TBK1 and structure-based designing of phytocompounds inhibitors for instigating the host immune response

Elucidating the binding mechanism of SARS-CoV-2 NSP6-TBK1 and structure-based designing of phytocompounds inhibitors for instigating the host immune response

SARS-CoV-2 VOCs, Mutational diversity and clinical outcome: Are they modulating drug efficacy by altered binding strength?

A multi‐tier computational screening framework to effectively search the mutational space of SARS‐CoV‐2 receptor binding motif to identify mutants with enhanced ACE2 binding abilities

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